In Vitro-in Silico Study on the Influence of Dose, Fraction Bioactivated and Endpoint Used on the Relative Potency Value of Pyrrolizidine Alkaloid N-oxides Compared to Parent Pyrrolizidine Alkaloids

Overview

Journal Curr Res Toxicol

Specialty Biology

Date 2024 Mar 12

PMID 38469320

Authors

Yasser Alhejji

Frances Widjaja

Shenghan Tian

Thomas Hoekstra

Sebastiaan Wesseling

Ivonne M C M Rietjens

Affiliations

Soon will be listed here.

Abstract

Pyrrolizidine alkaloids (PAs) and their N-oxides (PA-N-oxides) are phytotoxins found in food, feed and the environment. Yet, limited data exist from which the relative potency of a PA-N-oxide relative to its corresponding PA (REP) can be defined. This study aims to investigate the influence of dose, fraction bioactivated and endpoint on the REP of a series of pyrrolizidine N-oxides using in vitro-in silico data and physiologically based kinetic (PBK) modeling. The first endpoint used to calculate the REP was the ratio of the area under the concentration-time curve of PA resulting from an oral dose of PA-N-oxide divided by that from an equimolar dose of PA (Method 1). The second endpoint was the ratio of the amount of pyrrole-protein adducts formed under these conditions (Method 2). REP values appeared to decrease with increasing dose, with the decrease for Method 2 already starting at lower dose level than for Method 1. At dose levels as low as estimated daily human intakes, REP values amounted to 0.92, 0.81, 0.78, and 0.68 for retrorsine N-oxide, seneciphylline N-oxide, riddelliine N-oxide and senecivernine N-oxide, respectively, and became independent of the dose or fraction bioactivated, because no GSH depletion, saturation of PA clearance or PA-N-oxide reduction occurs. Overall, the results demonstrate the strength of using PBK modeling in defining REP values, thereby substantiating the use of the same approach for other PA-N-oxides for which in vivo data are lacking.

References

He X, Xia Q, Shi Q, Fu P . Metabolism of carcinogenic pyrrolizidine alkaloids and pyrrolizidine alkaloid -oxides by rat primary hepatocytes generate the same characteristic DHP-DNA adducts. J Environ Sci Health C Toxicol Carcinog. 2022; 39(4):357-372. DOI: 10.1080/26896583.2021.1954460. View

Ma J, Li M, Li N, Chan W, Lin G . Pyrrolizidine Alkaloid-Induced Hepatotoxicity Associated with the Formation of Reactive Metabolite-Derived Pyrrole-Protein Adducts. Toxins (Basel). 2021; 13(10). PMC: 8540779. DOI: 10.3390/toxins13100723. View

Tamta H, Pawar R, Wamer W, Grundel E, Krynitsky A, Rader J . Comparison of metabolism-mediated effects of pyrrolizidine alkaloids in a HepG2/C3A cell-S9 co-incubation system and quantification of their glutathione conjugates. Xenobiotica. 2012; 42(10):1038-48. DOI: 10.3109/00498254.2012.679978. View

HOSKINS L, ZAMCHECK N . Bacterial degradation of gastrointestinal mucins. I. Comparison of mucus constituents in the stools of germ-free and conventional rats. Gastroenterology. 1968; 54(2):210-7. View

Xia Q, Zhao Y, Lin G, Beland F, Cai L, Fu P . Pyrrolizidine Alkaloid-Protein Adducts: Potential Non-invasive Biomarkers of Pyrrolizidine Alkaloid-Induced Liver Toxicity and Exposure. Chem Res Toxicol. 2016; 29(8):1282-92. DOI: 10.1021/acs.chemrestox.6b00120. View

Chen L, Ning J, Louisse J, Wesseling S, Rietjens I . Use of physiologically based kinetic modelling-facilitated reverse dosimetry to convert in vitro cytotoxicity data to predicted in vivo liver toxicity of lasiocarpine and riddelliine in rat. Food Chem Toxicol. 2018; 116(Pt B):216-226. DOI: 10.1016/j.fct.2018.04.012. View

Xiong F, Jiang K, Chen Y, Ju Z, Yang L, Xiong A . Protein cross-linking in primary cultured mouse hepatocytes by dehydropyrrolizidine alkaloids: Structure-toxicity relationship. Toxicon. 2020; 186:4-11. DOI: 10.1016/j.toxicon.2020.07.015. View

Punt A, Freidig A, Delatour T, Scholz G, Boersma M, Schilter B . A physiologically based biokinetic (PBBK) model for estragole bioactivation and detoxification in rat. Toxicol Appl Pharmacol. 2008; 231(2):248-59. DOI: 10.1016/j.taap.2008.04.011. View

Yang M, Ruan J, Gao H, Li N, Ma J, Xue J . First evidence of pyrrolizidine alkaloid N-oxide-induced hepatic sinusoidal obstruction syndrome in humans. Arch Toxicol. 2017; 91(12):3913-3925. DOI: 10.1007/s00204-017-2013-y. View

10.

He X, Xia Q, Woodling K, Lin G, Fu P . Pyrrolizidine alkaloid-derived DNA adducts are common toxicological biomarkers of pyrrolizidine alkaloid N-oxides. J Food Drug Anal. 2017; 25(4):984-991. PMC: 9328871. DOI: 10.1016/j.jfda.2017.09.001. View

11.

Smith L, CULVENOR C . Plant sources of hepatotoxic pyrrolizidine alkaloids. J Nat Prod. 1981; 44(2):129-52. DOI: 10.1021/np50014a001. View

12.

Xia Q, Zhao Y, Von Tungeln L, Doerge D, Lin G, Cai L . Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity. Chem Res Toxicol. 2013; 26(9):1384-96. DOI: 10.1021/tx400241c. View

13.

Long F, Ji J, Wang X, Wang L, Chen T . LC-MS/MS method for determination of seneciphylline and its metabolite, seneciphylline N-oxide in rat plasma, and its application to a rat pharmacokinetic study. Biomed Chromatogr. 2021; 35(9):e5145. DOI: 10.1002/bmc.5145. View

14.

Griffin D, Segall H . Role of cellular calcium homeostasis in toxic liver injury induced by the pyrrolizidine alkaloid senecionine and the alkenal trans-4-OH-2-hexenal. J Biochem Toxicol. 1987; 2:155-67. DOI: 10.1002/jbt.2570020302. View

15.

Knutsen H, Alexander J, Barregard L, Bignami M, Bruschweiler B, Ceccatelli S . Risks for human health related to the presence of pyrrolizidine alkaloids in honey, tea, herbal infusions and food supplements. EFSA J. 2020; 15(7):e04908. PMC: 7010083. DOI: 10.2903/j.efsa.2017.4908. View

16.

Ji L, Chen Y, Wang Z . Intracellular glutathione plays important roles in pyrrolizidine alkaloid clivorine-induced toxicity on L-02 hepatocytes. Toxicol Mech Methods. 2009; 18(8):661-4. DOI: 10.1080/15376510802205726. View

17.

Williams L, Chou M, Yan J, Young J, Chan P, Doerge D . Toxicokinetics of riddelliine, a carcinogenic pyrrolizidine alkaloid, and metabolites in rats and mice. Toxicol Appl Pharmacol. 2002; 182(2):98-104. DOI: 10.1006/taap.2002.9441. View

18.

Wuilloud J, Gratze S, Gamble B, Wolnik K . Simultaneous analysis of hepatotoxic pyrrolizidine alkaloids and N-oxides in comfrey root by LC-ion trap mass spectrometry. Analyst. 2004; 129(2):150-6. DOI: 10.1039/b311030c. View

19.

Dusemund B, Nowak N, Sommerfeld C, Lindtner O, Schafer B, Lampen A . Risk assessment of pyrrolizidine alkaloids in food of plant and animal origin. Food Chem Toxicol. 2018; 115:63-72. DOI: 10.1016/j.fct.2018.03.005. View

20.

Ruan J, Gao H, Li N, Xue J, Chen J, Ke C . Blood Pyrrole-Protein Adducts--A Biomarker of Pyrrolizidine Alkaloid-Induced Liver Injury in Humans. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2015; 33(4):404-21. DOI: 10.1080/10590501.2015.1096882. View